HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells

Alexander Pietras; Loen M Hansford; A Sofie Johnsson; Esther Bridges; Jonas Sjölund; David Gisselsson; Matilda Rehn; Siv Beckman; Rosa Noguera; Samuel Navarro; Jörg Cammenga; Erik Fredlund; David R Kaplan; Sven Påhlman

doi:10.1073/pnas.0904606106

HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells

Alexander Pietras, Loen M Hansford, A Sofie Johnsson, Esther Bridges, Jonas Sjölund, David Gisselsson, Matilda Rehn, Siv Beckman, Rosa Noguera, Samuel Navarro, Jörg Cammenga, Erik Fredlund, David R Kaplan, Sven Påhlman

113 Citations (Scopus)

Abstract

High hypoxia-inducible factor-2alpha (HIF-2alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	106
Issue number	39
Pages (from-to)	16805-10
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.0904606106
Publication status	Published - 29 Sept 2009
Externally published	Yes

Keywords

Animals
Basic Helix-Loop-Helix Transcription Factors/genetics
Cell Differentiation
Cell Hypoxia
Cell Line, Tumor
Down-Regulation
Female
Humans
Mice
Mice, Nude
Neural Crest/metabolism
Neuroblastoma/metabolism
Vascular Endothelial Growth Factors/genetics

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Pietras, A., Hansford, L. M., Johnsson, A. S., Bridges, E., Sjölund, J., Gisselsson, D., Rehn, M., Beckman, S., Noguera, R., Navarro, S., Cammenga, J., Fredlund, E., Kaplan, D. R., & Påhlman, S. (2009). HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proceedings of the National Academy of Sciences of the United States of America, 106(39), 16805-10. https://doi.org/10.1073/pnas.0904606106

HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. / Pietras, Alexander; Hansford, Loen M; Johnsson, A Sofie et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 39, 29.09.2009, p. 16805-10.

Research output: Contribution to journal › Journal article › Research › peer-review

Pietras, A, Hansford, LM, Johnsson, AS, Bridges, E, Sjölund, J, Gisselsson, D, Rehn, M, Beckman, S, Noguera, R, Navarro, S, Cammenga, J, Fredlund, E, Kaplan, DR & Påhlman, S 2009, 'HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 39, pp. 16805-10. https://doi.org/10.1073/pnas.0904606106

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title = "HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells",

abstract = "High hypoxia-inducible factor-2alpha (HIF-2alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy.",

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T1 - HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells

AU - Pietras, Alexander

AU - Hansford, Loen M

AU - Johnsson, A Sofie

AU - Bridges, Esther

AU - Sjölund, Jonas

AU - Gisselsson, David

AU - Rehn, Matilda

AU - Beckman, Siv

AU - Noguera, Rosa

AU - Navarro, Samuel

AU - Cammenga, Jörg

AU - Fredlund, Erik

AU - Kaplan, David R

AU - Påhlman, Sven

PY - 2009/9/29

Y1 - 2009/9/29

N2 - High hypoxia-inducible factor-2alpha (HIF-2alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy.

AB - High hypoxia-inducible factor-2alpha (HIF-2alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors/genetics

KW - Cell Differentiation

KW - Cell Hypoxia

KW - Cell Line, Tumor

KW - Down-Regulation

KW - Female

KW - Humans

KW - Mice

KW - Mice, Nude

KW - Neural Crest/metabolism

KW - Neuroblastoma/metabolism

KW - Vascular Endothelial Growth Factors/genetics

U2 - 10.1073/pnas.0904606106

DO - 10.1073/pnas.0904606106

M3 - Journal article

C2 - 19805377

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EP - 16810

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 39

ER -

HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells

Abstract

Keywords

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